PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's investigational clinical candidate for the treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In nonclinical studies and a Phase 1 trial in healthy volunteers, PepGen's technology demonstrated significant improvement in the delivery of oligonucleotide resulting in higher levels of tissue concentrations and exon 51 skipping. Nuclear delivery of the EDO was confirmed in human tissue from the Phase 1 trial. The collective nonclinical and clinical data strongly suggest that repeat administration of PGN-EDO51 in people with DMD may lead to higher production of functional dystrophin, potentially resulting in improved clinical outcomes over time. PepGen's Phase 2 clinical program includes 2 studies: CONNECT1-EDO51, an open-label multiple-ascending dose (MAD) study being conducted in Canada, and CONNECT2-EDO51, a multinational randomized placebo-controlled MAD study. Participants who complete the MAD period in either study will have the opportunity to continue dosing in an open-label, long-term extension. The primary objectives of CONNECT2-EDO51 are to evaluate the safety and tolerability of PGN-EDO51 and to determine dystrophin levels following repeat dosing in male participants with DMD amenable to exon 51 skipping. Secondary objectives are plasma pharmacokinetics (PK) and concentration of PGN-EDO51 in muscle tissue. Muscle biopsies occur at Baseline and Week 25. Main inclusion criteria are age ≥6 years with a confirmed genetic diagnosis of DMD amenable to exon 51 skipping, and weight ≥25 kg. Participants will be randomized 3:1 to receive either PGN-EDO51 or placebo in multiple ascending doses across 3 cohorts. All participants (N=20) will receive 7 doses at approximately 4-week intervals over 24 weeks. The study design will be presented.

PepGen's Enhanced Delivery Oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's investigational candidate for the treatment of people with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In mdx mice, a single intravenous (IV) dose of 30 or 60 mg/kg PGN-EDO23 (a murine analogue of PGN-EDO51) resulted in dose-dependent high levels of exon skipping and dystrophin production in biceps. Additionally, four monthly doses in mdx mice (30 mg/kg) resulted in significant increase in exon skipping levels (91.5%) and dystrophin production (82.2%) suggesting accumulation of dystrophin with repeat dosing. Importantly, dystrophin was uniformly distributed across muscle and resulted in 97.1% dystrophin positive fibers following repeat dosing. In NHPs, a single IV dose of PGN-EDO51 resulted in dose-dependent exon 51 skipping in biceps. Similar to what was seen in mice, four monthly doses of PGN-EDO51 resulted in dose-dependent accumulation of skipped transcripts. Levels of exon 51 skipping in biceps observed after a single dose, were increased by 14-fold following four 20 mg/kg monthly doses in NHPs. Toxicology studies in NHPs indicated repeat dosing with PGN-EDO51 was generally safe and well tolerated. No persistent elevation of kidney biomarkers was observed at doses through 45 mg/kg. Additionally, there were no adverse findings in the kidney after 11 monthly 45 mg/kg doses, no notable hematologic or hepatic effects, and no cardiovascular effects. Combined, these data suggest monthly repeat dosing of PGN-EDO51 may result in dystrophin accumulation, which may potentially result in a clinically meaningful benefit in people with DMD amenable to exon 51 skipping. These data informed the design of the ongoing Phase 2, multiple-ascending dose studies, CONNECT1-EDO51 and CONNECT2-EDO51.

PepGen's Enhanced Delivery Oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDODM1, in clinical trials for the treatment of myotonic dystrophy type 1 (DM1), is designed to bind pathogenic CUG repeat expansions in DMPK mRNA and liberate MBNL1 protein without degrading DMPK transcripts. Liberation of sequestered MBNL1 is expected to restore the normal splicing of multiple downstream transcripts; a central cause of DM1 pathology. Indeed, in vitro treatment of DM1 myotubes showed PGN-EDODM1 delivery to the nucleus, and treatment of DM1 patient myotubes with both low-CUG and high-CUG repeats demonstrated similar dose-dependent reduction of pathogenic myonuclear foci, liberation of MBNL1 from foci, and correction of mis-splicing without DMPK RNA degradation. A single intravenous (IV) dose of PGN-EDODM1 to HSALR mice resulted in dose-dependent correction of mis-splicing and improvement in myotonia. Following repeat-dosing of PGN-EDODM1 once every 4 weeks, near complete resolution of DM1 pathology including correction of mis-splicing and resolution of myotonia was observed. Toxicology studies in NHPs indicate repeat dosing with PGN-EDODM1 was generally safe and well tolerated. No persistent elevation of kidney biomarkers was observed at doses through 60 mg/kg. Additionally, there were no adverse findings in the kidney after 4 monthly doses of 60 mg/kg, nor notable hematologic or hepatic or cardiovascular effects. Currently, there are no approved therapies for DM1. Nonclinical pharmacology and safety studies with PGN-EDODM1 showed meaningful therapeutic potential on splicing correction and myotonia correction and support the ongoing Phase 1 single-ascending dose study FREEDOM-DM1 in adults with DM1.

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's investigational clinical candidate for the treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In nonclinical studies and a Phase 1 trial in healthy volunteers, PepGen's technology demonstrated significant improvement in the delivery of oligonucleotides resulting in higher levels of tissue concentrations and exon 51 skipping. Nuclear delivery of the EDO was confirmed in human tissue from the Phase 1 trial. Collective nonclinical and clinical data strongly suggest that repeat administration of PGN-EDO51 in people with DMD may lead to higher production of functional dystrophin, potentially resulting in improved clinical outcomes. PepGen's Phase 2 clinical program includes 2 studies: CONNECT1-EDO51, an open-label multiple-ascending dose (MAD) study being conducted in Canada (NCT06079736), and CONNECT2-EDO51, a multinational randomized placebo-controlled MAD study. Participants who complete the MAD period in either study will have the opportunity to continue dosing in a long-term extension. The CONNECT1-EDO51 study objective is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (dystrophin, exon skipping) of PGN-EDO51 following repeat dosing in male participants with DMD amenable to exon 51 skipping. Muscle biopsies are taken at Baseline and Week 13. Main inclusion criteria are age ≥8 years with a confirmed genetic diagnosis of DMD amenable to exon 51 skipping, and weight ≥25 kg. Participants will receive PGN-EDO51 in ascending doses across 3 cohorts. All participants (N=10) will receive 4 doses of PGN-EDO51 at approximately 4-week intervals over 12 weeks. Participants in the first cohort have received repeat doses of 5 mg/kg PGN-EDO51. Safety and initial dystrophin results from this cohort will be presented.

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides PGN-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1). PGN-EDODM1 binds to toxic CUG repeat expansion (CUGexp) in DMPK mRNA and acts to liberate sequestered MBNL1 protein without degrading DMPK transcript. Release of MBNL1 protein is hypothesized to restore the splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology. Men and women, 18-50 years of age, inclusive, with genetically confirmed diagnosis of DM1 will be randomized 3:1 (6 active, 2 placebo) to receive PGN EDODM1 or placebo in each dose cohort. The primary objective of this single-ascending dose (SAD) study is to evaluate the safety and tolerability of PGN-EDODM1 in adults living with DM1. Secondary and exploratory objectives include pharmacokinetics (PK), concentration of PGN-EDODM1 in skeletal muscle, and pharmacodynamics (changes in splicing pattern of affected transcripts). A muscle needle biopsy (tibialis anterior) will be performed at baseline and at Weeks 4 and 16 post-dosing for measurement of tissue drug concentrations and splicing of selected transcripts. Exploratory measures such as video hand opening time to assess myotonia and functional measures will be included to inform future studies. This Phase 1 SAD clinical study will support continued development of PGN-EDODM1 for the treatment of the root cause of DM1. PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides PGN-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1). PGN-EDODM1 binds to toxic CUG repeat expansion (CUGexp) in DMPK mRNA and acts to liberate sequestered MBNL1 protein without degrading DMPK transcript. Release of MBNL1 protein is hypothesized to restore the splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology. Men and women, 18-50 years of age, inclusive, with genetically confirmed diagnosis of DM1 will be randomized 3:1 (6 active, 2 placebo) to receive PGN EDODM1 or placebo in each dose cohort. The primary objective of this single-ascending dose (SAD) study is to evaluate the safety and tolerability of PGN-EDODM1 in adults living with DM1. Secondary and exploratory objectives include pharmacokinetics (PK), concentration of PGN-EDODM1 in skeletal muscle, and pharmacodynamics (changes in splicing pattern of affected transcripts). A muscle needle biopsy (tibialis anterior) will be performed at baseline and at Weeks 4 and 16 post-dosing for measurement of tissue drug concentrations and splicing of selected transcripts. Exploratory measures such as video hand opening time to assess myotonia and functional measures will be included to inform future studies. This Phase 1 SAD clinical study will support continued development of PGN-EDODM1 for the treatment of the root cause of DM1.

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's clinical candidate for the treatment of people with DMD amenable to exon 51 skipping. In the mdx mouse model of DMD, a single intravenous (IV) dose of 30 or 60 mg/kg of mPGN EDO23 (mouse analogue of PGN-EDO51) resulted in exon skipping levels of 52.5% and 82.8% and dystrophin protein production of 22.5% and 51.7% in biceps. Pharmacological activity was detectable in biceps for up to 12 weeks after the single dose. Repeat dosing (30 mg/kg mPGN EDO23 once every 4 weeks for 4 doses) in mdx mice resulted in higher levels of exon skipping (91.5%) and dystrophin protein (82.3%) suggesting accumulation in biceps with repeat dosing. A single IV dose of PGN-EDO51 in non-human primates (NHP) resulted in dose-dependent exon 51 skipping (by RT-PCR and ddPCR) in biceps. Repeat dosing every 4 weeks resulted in dose-dependent accumulation of exon 51 skipping (by ddPCR) in biceps. Levels of exon 51 skipping (by ddPCR) in biceps observed after a single dose increased by 14-fold at 20 mg/kg and 3.4-fold at 30mg/kg with repeat dosing. Comparative pharmacology data show 5.9- to 12.9-fold higher levels of exon skipping in biceps following single IV doses of mPGN-EDO23 (mdx) and PGN-EDO51 (NHP) compared to comparator compounds PPMOs R6G-PMO23 (mdx) and R6G-PMO51 (NHP). Combined, the nonclinical studies show significant accumulation of exon skipping and dystrophin protein after repeat doses in the mdx mouse model and accumulation of exon skipping in NHPs. These data suggest repeat PGN-EDO51 dosing every 4 weeks may result in dystrophin accumulation potentially resulting in a clinically meaningful benefit in people with DMD amenable to exon 51 skipping and informed the design of CONNECT-EDO51 Phase 2, multiple-ascending dose studies. PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's clinical candidate for the treatment of people with DMD amenable to exon 51 skipping. In the mdx mouse model of DMD, a single intravenous (IV) dose of 30 or 60 mg/kg of mPGN EDO23 (mouse analogue of PGN-EDO51) resulted in exon skipping levels of 52.5% and 82.8% and dystrophin protein production of 22.5% and 51.7% in biceps. Pharmacological activity was detectable in biceps for up to 12 weeks after the single dose. Repeat dosing (30 mg/kg mPGN EDO23 once every 4 weeks for 4 doses) in mdx mice resulted in higher levels of exon skipping (91.5%) and dystrophin protein (82.3%) suggesting accumulation in biceps with repeat dosing. A single IV dose of PGN-EDO51 in non-human primates (NHP) resulted in dose-dependent exon 51 skipping (by RT-PCR and ddPCR) in biceps. Repeat dosing every 4 weeks resulted in dose-dependent accumulation of exon 51 skipping (by ddPCR) in biceps. Levels of exon 51 skipping (by ddPCR) in biceps observed after a single dose increased by 14-fold at 20 mg/kg and 3.4-fold at 30mg/kg with repeat dosing. Comparative pharmacology data show 5.9- to 12.9-fold higher levels of exon skipping in biceps following single IV doses of mPGN-EDO23 (mdx) and PGN-EDO51 (NHP) compared to comparator compounds PPMOs R6G-PMO23 (mdx) and R6G-PMO51 (NHP). Combined, the nonclinical studies show significant accumulation of exon skipping and dystrophin protein after repeat doses in the mdx mouse model and accumulation of exon skipping in NHPs. These data suggest repeat PGN-EDO51 dosing every 4 weeks may result in dystrophin accumulation potentially resulting in a clinically meaningful benefit in people with DMD amenable to exon 51 skipping and informed the design of CONNECT-EDO51 Phase 2, multiple-ascending dose studies.

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides.PGN-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1).PGN-EDODM1 binds to toxic CUG repeat expansion (CUGexp) in DMPK mRNA and acts to liberate sequestered MBNL1 protein without degrading DMPK transcript.Liberation of MBNL1 is hypothesized to restore splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology.PGN-EDODM1 pharmacology was characterized using human immortalized myoblasts and the HSALR transgenic mouse model of DM1, and nonhuman primates (NHPs) were used to evaluate DMPK levels.Control and DM1 myoblasts ( ∼2600 CTGexp) were differentiated and treated with PGN EDODM1, which resulted in dose-dependent reduction in pathogenic myonuclear foci, liberation of MBNL1 from foci, and correction of mis-splicing in DM1 cells, while DMPK levels remained unchanged.Single intravenous (IV) dose of PGN-EDODM1 or control administered to HSALR mice resulted in high muscle concentrations of PGN-EDODM1, resolution of myotonia, dose-dependent correction of mis-splicing, and no significant impact on HSA expression when evaluated 2-weeks postdose.Splicing correction in HSALR mice persisted up to 24 weeks.Additional data from a repeat-dose study in HSALR mice with low PGN EDODM1 doses will be presented.Repeat IV doses of PGN-EDODM1 or control administered to NHPs every 2 weeks (10, 30, or 60mg/kg) or every 4 weeks (60mg/kg) did not result in decreases in DMPK transcript levels when evaluated 1 week after the final dose.Currently, there are no approved therapies for DM1.Nonclinical pharmacology studies with PGN-EDODM1 showed considerable therapeutic potential.Nonclinical data support the Phase 1 single-ascending dose study in adults with DM1.

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDO53, PGN-EDO45, and PGN-EDO44 are being evaluated for potential treatment of Duchenne muscular dystrophy (DMD) subpopulations amenable to exon 53, exon 45, or exon 44 skipping, respectively. Wild-type human myoblasts were dosed with PGN-EDO45 versus R6G-PMO45 (comparator PPMO), and with PGN-EDO44. High levels of exon skipping were seen for both EDO candidates. At the highest dose level evaluated in this in vitro system, PGN-EDO45 demonstrated mean exon 45 skipping levels of 79.9%. PGN-EDO45 was observed to produce higher levels of exon skipping compared to R6G-PMO45 at every dose level, with R6G-PMO45 observed to yield only 54.0% of exon 45 skipped transcript at the highest dose level. PGN-EDO44 demonstrated mean exon 44 skipping levels of 93.4% at the highest dose level assessed. Pharmacological activity profiles were evaluated for PGN-EDO53 in non-human primates (NHPs). A single intravenous (IV) dose of PGN-EDO53 in NHPs showed mean exon skipping levels of 36.4% in biceps, approximately 7-fold higher as compared with 5% exon 53 skipping after R6G-PMO53 dosing (comparator PPMO). Following 3 IV doses of PGN-EDO53 administered every 4 weeks, mean exon skipping levels in biceps were observed to be 57.2%. By comparison, mean exon skipping levels in biceps with R6G-PMO53 (comparator PPMO) administered every 4 weeks were 20.8%, ∼3-fold lower than with PGN-EDO53. Combined, the nonclinical data support further development of PGN-EDO53, PGN-EDO45 and PGN-EDO44. This next generation of oligonucleotide therapies for DMD show significant potential to transform the treatment of severe neuromuscular diseases. PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDO53, PGN-EDO45, and PGN-EDO44 are being evaluated for potential treatment of Duchenne muscular dystrophy (DMD) subpopulations amenable to exon 53, exon 45, or exon 44 skipping, respectively. Wild-type human myoblasts were dosed with PGN-EDO45 versus R6G-PMO45 (comparator PPMO), and with PGN-EDO44. High levels of exon skipping were seen for both EDO candidates. At the highest dose level evaluated in this in vitro system, PGN-EDO45 demonstrated mean exon 45 skipping levels of 79.9%. PGN-EDO45 was observed to produce higher levels of exon skipping compared to R6G-PMO45 at every dose level, with R6G-PMO45 observed to yield only 54.0% of exon 45 skipped transcript at the highest dose level. PGN-EDO44 demonstrated mean exon 44 skipping levels of 93.4% at the highest dose level assessed. Pharmacological activity profiles were evaluated for PGN-EDO53 in non-human primates (NHPs). A single intravenous (IV) dose of PGN-EDO53 in NHPs showed mean exon skipping levels of 36.4% in biceps, approximately 7-fold higher as compared with 5% exon 53 skipping after R6G-PMO53 dosing (comparator PPMO). Following 3 IV doses of PGN-EDO53 administered every 4 weeks, mean exon skipping levels in biceps were observed to be 57.2%. By comparison, mean exon skipping levels in biceps with R6G-PMO53 (comparator PPMO) administered every 4 weeks were 20.8%, ∼3-fold lower than with PGN-EDO53. Combined, the nonclinical data support further development of PGN-EDO53, PGN-EDO45 and PGN-EDO44. This next generation of oligonucleotide therapies for DMD show significant potential to transform the treatment of severe neuromuscular diseases.

included serum chemistries (alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, bilirubin) and dystrophin expression (western blot [WB], immunofluorescence [IF]).No treatment-related adverse events were observed, including abnormal histopathology.WB/IF evaluation showed that dystrophin expression and localization at the sarcolemma were not adversely impacted by sequential treatment.These preclinical results support the safety of sequential administration and dystrophin expression consistent with individual treatment, suggesting that patients may be able to receive continuous exonskipping therapy prior to GT.

Delandistrogene moxeparvovec (SRP-9001) is an investigational rAAV vectorbased gene therapy, designed to compensate for missing functional dystrophin in Duchenne muscular dystrophy (DMD) by delivering a transgene encoding SRP-9001 dystrophin, an engineered dystrophin protein that retains key functional domains of the wild-type protein.Drawing on delandistrogene moxeparvovec clinical trial experience (Study 101 [SRP-9001-101; NCT03375164], Study 102 [SRP-9001-102; NCT03769116], and ENDEAVOR [Study 103; NCT04626674]), we outline several practical considerations for delandistrogene moxeparvovec administration in patients with DMD, including the observed time course of events, monitoring for and management of adverse events, and mitigation strategies.Considerations for initiating delandistrogene moxeparvovec treatment in patients with DMD include: (1) screening for elevated levels of anti-rAAVrh74 total binding antibodies before infusion; (2) assessing liver function, platelet count, and troponin I levels before administration; (3) monitoring liver function weekly (first 3 months post-infusion) and, if indicated, continuing monitoring until results are unremarkable; (4) postponing administration for patients with acute liver disease until disease control/resolution; (5) monitoring troponin I levels weekly (first month post-infusion), and continuing monitoring if indicated; and (6) administering corticosteroids starting 1 day prior to infusion (for patients already on corticosteroids), and maintaining the corticosteroid regimen for at least 60 days post-infusion, unless earlier tapering is indicated.Though the safety profile of delandistrogene moxeparvovec to date has been relatively consistent, monitorable, and manageable, clinical trial experience has led to important learnings and practical considerations that may mitigate the risk of adverse events following administration of delandistrogene moxeparvovec.

PGN-EDO51 is PepGen's clinical candidate to treat individuals with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. It is the first of a series of therapies based on our Enhanced Delivery Oligonucleotide (EDO) platform and will be followed by programs to address myotonic dystrophy type one, other subgroups of DMD and other neuromuscular and neurological disorders. Therapeutic oligonucleotides are precision medicines that modulate the genetic machinery and have shown great promise in treating genetic disorders. First generation oligonucleotides resulted in suboptimal delivery to muscle and therefore afford limited dystrophin production and limited therapeutic benefit in people with DMD. PepGen's EDO technology efficiently and effectively delivers oligonucleotides to skeletal, smooth and cardiac muscle, offering great promise for neuromuscular diseases. Studies in the mdx mouse model of DMD demonstrated robust dystrophin production in key tissues following a single administration, inducing 91% of normal levels in quadriceps seven days after dosing. Single dose studies in non-human primates (NHPs) established that PGN-EDO51 leads to robust exon skipping in muscle and drives broad biodistribution, with significant levels detected in skeletal, smooth and cardiac muscles and in CNS tissues. Repeat dose studies in NHPs demonstrated that exon skipping levels accumulate. Following three doses of 30 mg/kg, exon skipping levels of 78% in biceps, 76% in diaphragm and 24% in left ventricle were obtained. PGN-EDO51 was well tolerated at target doses, and clinical trials enabling toxicology studies have been completed. The high levels of activity and the tolerability of our approach demonstrated by the totality of studies supported our Clinical Trial Application to Health Canada and the initiation of our Phase 1 clinical trial in early 2022. Results from this Phase 1 safety study in healthy volunteers and plans for our Phase 2 studies will be discussed. PGN-EDO51 is PepGen's clinical candidate to treat individuals with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. It is the first of a series of therapies based on our Enhanced Delivery Oligonucleotide (EDO) platform and will be followed by programs to address myotonic dystrophy type one, other subgroups of DMD and other neuromuscular and neurological disorders. Therapeutic oligonucleotides are precision medicines that modulate the genetic machinery and have shown great promise in treating genetic disorders. First generation oligonucleotides resulted in suboptimal delivery to muscle and therefore afford limited dystrophin production and limited therapeutic benefit in people with DMD. PepGen's EDO technology efficiently and effectively delivers oligonucleotides to skeletal, smooth and cardiac muscle, offering great promise for neuromuscular diseases. Studies in the mdx mouse model of DMD demonstrated robust dystrophin production in key tissues following a single administration, inducing 91% of normal levels in quadriceps seven days after dosing. Single dose studies in non-human primates (NHPs) established that PGN-EDO51 leads to robust exon skipping in muscle and drives broad biodistribution, with significant levels detected in skeletal, smooth and cardiac muscles and in CNS tissues. Repeat dose studies in NHPs demonstrated that exon skipping levels accumulate. Following three doses of 30 mg/kg, exon skipping levels of 78% in biceps, 76% in diaphragm and 24% in left ventricle were obtained. PGN-EDO51 was well tolerated at target doses, and clinical trials enabling toxicology studies have been completed. The high levels of activity and the tolerability of our approach demonstrated by the totality of studies supported our Clinical Trial Application to Health Canada and the initiation of our Phase 1 clinical trial in early 2022. Results from this Phase 1 safety study in healthy volunteers and plans for our Phase 2 studies will be discussed.